tbuckley/cabot-search huggingface dataset:
Surgery with locking plate or hemiarthroplasty versus nonoperative treatment of 3–4-part proximal humerus fractures in older patients (NITEP): An open-label randomized trial
Authors: Antti P. Launonen, Bakir O. Sumrein, Aleksi Reito, Vesa Lepola, Juha Paloneva, Hans E. Berg, Li Felländer-Tsai, Kristo Kask, Timo Rahnel, Kaspar Tootsi, Aare Märtson, Kenneth B. Jonsson, Olof Wolf, Peter Ström, Kaj Døssing, Helle K. Østergaard, Inger Mechlenburg, Ville M. Mattila, Minna K. Laitinen
Journal: PLoS Medicine (2023)

Background Proximal humerus fractures (PHFs) are common fractures, especially in older female patients. These fractures are commonly treated surgically, but the consensus on the best treatment is still lacking. Methods and findings The primary aim of this multicenter, randomized 3-arm superiority, open-label trial was to assess the results of nonoperative treatment and operative treatment either with locking plate (LP) or hemiarthroplasty (HA) of 3- and 4-part PHF with the primary outcome of Disabilities of the Arm, Shoulder, and Hand (DASH) at 2-year follow-up. Between February 2011 and December 2019, 160 patients 60 years and older with 3- and 4-part PHFs were randomly assigned in 1:1:1 fashion in block size of 10 to undergo nonoperative treatment (control) or operative intervention with LP or HA. In total, 54 patients were assigned to the nonoperative group, 52 to the LP group, and 54 to the HA group. Five patients assigned to the LP group were reassigned to the HA group perioperatively due to high comminution, and all of these patients had 4-part fractures. In the intention-to-treat analysis, there were 42 patients in the nonoperative group, 44 in the LP group, and 37 in the HA group. The outcome assessors were blinded to the study group. The mean DASH score at 2-year follow-up was 30.4 (standard error (SE) 3.25), 31.4 (SE 3.11), and 26.6 (SE 3.23) points for the nonoperative, LP, and HA groups, respectively. At 2 years, the between-group differences were 1.07 points (95% CI [−9.5,11.7]; p = 0.97) between nonoperative and LP, 3.78 points (95% CI [−7.0,14.6]; p = 0.69) between nonoperative and HA, and 4.84 points (95% CI [−5.7,15.4]; p = 0.53) between LP and HA. No significant differences in primary or secondary outcomes were seen in stratified age groups (60 to 70 years and 71 years and over). At 2 years, we found 30 complications (3/52, 5.8% in nonoperative; 22/49, 45% in LP; and 5/49, 10% in HA group, p = 0.0004) and 16 severe pain-related adverse events. There was a revision rate of 22% in the LP group. The limitation of the trial was that the recruitment period was longer than expected due to a high number of exclusions after the assessment of eligibility and a larger exclusion rate than anticipated toward the end of the trial. Therefore, the trial was ended prematurely. Conclusions In this study, no benefit was observed between operative treatment with LP or HA and nonoperative treatment in displaced 3- and 4-part PHFs in patients aged 60 years and older. Further, we observed a high rate of complications related to operative treatments. Trial Registration ClinicalTrials.gov NCT01246167 .
Lumbosacral Paravertebral Tophaceous Gout on an Adolescent Mimicking Malignant Neoplasm in 18F-FDG PET/CT
Authors: Benzheng Jiao, Shanshan Liu, Yuying Zhuang, Shuangyan Zhao, Hongguang Zhao
Journal: Clinical Nuclear Medicine (2023)

Contrast-enhanced MRI was performed on a 17-year-old adolescent boy with chronic lumbar and lower-limb pain, which had worsened over the past 3 days. It revealed a suspicious malignant mass adjacent to right appendage of L5-S1 vertebrae, with mixed signals and heterogeneous and obvious enhancement. 18 F-FDG PET/CT was subsequently performed for staging. It showed an FDG-avid mass with mixed density in right psoas major muscle, involving adjacent appendage of L5-S1 vertebrae. Histopathological examination confirmed the mass to be gouty tophus, characterized by nodular homogeneous pink amorphous deposits around the cartilage tissue, surrounded by histiocytes and multinucleated giant cells.
Conspecific versus heterospecific transmission shapes host specialization of the phyllosphere microbiome
Authors: Kyle M. Meyer, Isabella E. Muscettola, Ana Luisa S. Vasconcelos, Julia K. Sherman, C. Jessica E. Metcalf, Steven E. Lindow, Britt Koskella
Journal: Cell Host & Microbe (2023)

In disease ecology, pathogen transmission among conspecific versus heterospecific hosts is known to shape pathogen specialization and virulence, but we do not yet know if similar effects occur at the microbiome level. We tested this idea by experimentally passaging leaf-associated microbiomes either within conspecific or across heterospecific plant hosts. Although conspecific transmission results in persistent host-filtering effects and more within-microbiome network connections, heterospecific transmission results in weaker host-filtering effects but higher levels of interconnectivity. When transplanted onto novel plants, heterospecific lines are less differentiated by host species than conspecific lines, suggesting a shift toward microbiome generalism. Finally, conspecific lines from tomato exhibit a competitive advantage on tomato hosts against those passaged on bean or pepper, suggesting microbiome-level host specialization. Overall, we find that transmission mode and previous host history shape microbiome diversity, with repeated conspecific transmission driving microbiome specialization and repeated heterospecific transmission promoting microbiome generalism.
Author Correction: Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression
Authors: Hanane Laklai, Yekaterina A. Miroshnikova, Michael W. Pickup, Eric A. Collisson, Grace E. Kim, Alex S. Barrett, Ryan C. Hill, Johnathon N. Lakins, David D. Schlaepfer, Janna K. Mouw, Valerie S. LeBleu, Nilotpal Roy, Sergey V. Novitskiy, Julia S. Johansen, Valeria Poli, Raghu Kalluri, Christine A. Iacobuzio-Donahue, Laura D. Wood, Matthias Hebrok, Kirk Hansen, Harold L. Moses, Valerie M. Weaver
Journal: Nature Medicine (2023)
<scp>R‐miniCHOP</scp> versus <scp>R‐CHOP</scp> in elderly patients with diffuse large B‐cell lymphoma: A propensity matched population‐based study
Authors: D. Al‐Sarayfi, M. Brink, M. E. D. Chamuleau, R. Brouwer, R. S. van Rijn, D. Issa, W. Deenik, G. Huls, R. Mous, J. S. P. Vermaat, A. Diepstra, J. M. Zijlstra, T. van Meerten, M. Nijland
Journal: American Journal of Hematology (2023)

For elderly frail patients with diffuse large B-cell lymphoma (DLBCL), an attenuated chemo-immunotherapy strategy of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-miniCHOP) was introduced as a treatment option as from 2014 onward in the Netherlands. Although R-miniCHOP is more tolerable, reduction of chemotherapy could negatively affect survival compared to R-CHOP. The aim of this analysis was to assess survival of patients treated with R-miniCHOP compared to R-CHOP. DLBCL patients ≥65 years, newly diagnosed in 2014-2020, who received ≥1 cycle of R-miniCHOP or R-CHOP were identified in the Netherlands Cancer Registry, with survival follow-up through 2022. Patients were propensity-score-matched for baseline characteristics. Main endpoints were progression-free survival (PFS), overall survival (OS), and relative survival (RS). The use of R-miniCHOP in DLBCL increased from 2% in 2014 to 15% in 2020. In total, 384 patients treated with R-miniCHOP and 384 patients treated with R-CHOP were included for comparison (median age; 81 years, stage 3-4; 68%). The median number of R-(mini)CHOP cycles was 6 (range, 1-8). The 2-year PFS, OS and RS were inferior for patients treated with R-miniCHOP compared to R-CHOP (PFS 51% vs. 68%, p < .01; OS 60% vs. 75%, p < .01; RS 69% vs. 86%, p < .01). In multivariable analysis, patients treated with R-miniCHOP had higher risk of all-cause mortality compared to patients treated with R-CHOP (HR 1.73; 95%CI, 1.39-2.17). R-miniCHOP is effective for most elderly patients. Although survival is inferior compared to R-CHOP, the use of R-miniCHOP as initial treatment is increasing. Therefore, fitness needs to be carefully weighed in treatment selection.
Transcriptional landscape of macrophages in cutaneous graft-versus-host disease
Authors: Thomas Döbel, Knut Schäkel
Journal: British Journal of Dermatology (2023)

We are submitting a comment on a study authored by: J. Strobel, L. M. Gail, L. Krecu, S. Madad, L. Kleissl, L. Unterluggauer, A. Redl, K. Brazdilova, S. Saluzzo, P. Wohlfarth, H. A. Knaus, M. Mitterbauer, W. Rabitsch, M. Haniffa and G. Stary, "Diverse macrophage populations contribute to distinct manifestations of human cutaneous graft-versus-host disease," British Journal of Dermatology, 2023.
Sustained response off‐treatment in eltrombopag‐treated adult patients with <scp>ITP</scp> who are refractory or relapsed after first‐line steroids: Primary, final, and ad‐hoc analyses of the Phase <scp>II TAPER</scp> trial
Authors: Nichola Cooper, Waleed Ghanima, Nicola Vianelli, David Valcárcel, İrfan Yavaşoğlu, Anait Melikyan, Eduardo Yañez Ruiz, Jens Haenig, Olivier Somenzi, James Lee, Joan Clark, Yifan Zhang, Francesco Zaja
Journal: American Journal of Hematology (2023)

Abstract Immune thrombocytopenia (ITP) is characterized by reduced platelet count due to increased destruction and is categorized according to the time following diagnosis (newly diagnosed, persistent, chronic). First‐line corticosteroid therapy is associated with transient response, high relapse rates, and considerable toxicity. TAPER (NCT03524612) is a Phase II, prospective, single‐arm trial investigating whether eltrombopag can induce a sustained response off‐treatment (SRoT) in adult patients with ITP after first‐line corticosteroid failure. This study defines SRoT as an off‐treatment period wherein platelet count remains above 30 × 10 9 /L in the absence of bleeding or rescue therapy. The primary endpoint was the proportion of patients who achieved SRoT until Month 12, which was 30.5% ( n = 32/105; p &lt; .0001 testing hypothesis H1: proportion &gt;15%) following eltrombopag tapering and discontinuation, and median SRoT duration was ~8 months until Month 12. Median platelet count increased within 1 month of treatment and remained elevated until Month 12. Quality of life improved within 3 months and was maintained. Headache (21%) was the most common adverse event. None of the 4 deaths reported were considered treatment‐related. In summary, ~one‐third of patients achieved SRoT until Month 12 following eltrombopag tapering and discontinuation. An ad‐hoc early‐use analysis, stratified by ITP duration at baseline, assessed initial hematologic responses and safety. Results suggest that eltrombopag has similar efficacy in newly diagnosed and later stages of ITP. In follow‐up until Month 24, a median SRoT duration of ~22 months was observed ( n = 20). The safety profile was comparable across analyses and ITP duration groups and aligned with its well‐established safety profile.
Mind the Viscous Modulus: The Mechanotransductive Response to the Viscous Nature of Isoelastic Matrices Regulates Stem Cell Chondrogenesis
Authors: Matthew Walker, Eonan William Pringle, Giuseppe Ciccone, Lluís Oliver‐Cervelló, Manlio Tassieri, Delphine Gourdon, Marco Cantini
Journal: Advanced Healthcare Materials (2023)

The design of hydrogels as mimetics of tissues' matrices typically disregards the viscous nature of native tissues and focuses only on their elastic properties. In the case of stem cell chondrogenesis, this has led to contradictory results, likely due to unreported changes in the matrices' viscous modulus. Here, by employing isoelastic matrices with Young's modulus of ≈12 kPa, variations in viscous properties alone (i.e., loss tangent between 0.1 and 0.25) are demonstrated to be sufficient to drive efficient growth factor-free chondrogenesis of human mesenchymal stem cells, both in 2D and 3D cultures. The increase of the viscous component of RGD-functionalized polyacrylamide or polyethylene glycol maleimide hydrogels promotes a phenotype with reduced adhesion, alters mechanosensitive signaling, and boosts cell-cell contacts. In turn, this upregulates the chondrogenic transcription factor SOX9 and supports neocartilage formation, demonstrating that the mechanotransductive response to the viscous nature of the matrix can be harnessed to direct cell fate.
The ecological and evolutionary consequences of tropicalisation
Authors: Karolina M. Zarzyczny, Marc Rius, Suzanne T. Williams, Phillip B. Fenberg
Journal: Trends in Ecology & Evolution (2023)

Tropicalisation is a marine phenomenon arising from contemporary climate change, and is characterised by the range expansion of tropical/subtropical species and the retraction of temperate species. Tropicalisation occurs globally and can be detected in both tropical/temperate transition zones and temperate regions. The ecological consequences of tropicalisation range from single-species impacts (e.g., altered behaviour) to whole ecosystem changes (e.g., phase shifts in intertidal and subtidal habitats). Our understanding of the evolutionary consequences of tropicalisation is limited, but emerging evidence suggests that tropicalisation could induce phenotypic change as well as shifts in the genotypic composition of both expanding and retracting species. Given the rapid rate of contemporary climate change, research on tropicalisation focusing on shifts in ecosystem functioning, biodiversity change, and socioeconomic impacts is urgently needed.
Recommendations for quantitative uncertainty consideration in ecology and evolution
Authors: Emily G. Simmonds, Kwaku P. Adjei, Benjamin Cretois, Lisa Dickel, Ricardo González-Gil, Jack H. Laverick, Caitlin P. Mandeville, Elizabeth G. Mandeville, Otso Ovaskainen, Jorge Sicacha-Parada, Emma S. Skarstein, Bob O'Hara
Journal: Trends in Ecology & Evolution (2023)

<h2>Abstract</h2> Ecological and evolutionary studies are currently failing to achieve complete and consistent reporting of model-related uncertainty. We identify three key barriers – a focus on parameter-related uncertainty, obscure uncertainty metrics, and limited recognition of uncertainty propagation – which have led to gaps in uncertainty consideration. However, these gaps can be closed. We propose that uncertainty reporting in ecology and evolution can be improved through wider application of existing statistical solutions and by adopting good practice from other scientific fields. Our recommendations include greater consideration of input data and model structure uncertainties, field-specific uncertainty standards for methods and reporting, and increased uncertainty propagation through the use of hierarchical models.
A phenome-wide scan reveals convergence of common and rare variant associations
Authors: Dan Zhou, Yuan Zhou, Yue Xu, Ran Meng, Eric R. Gamazon
Journal: Genome Medicine (2023)

Common and rare variants contribute to the etiology of complex traits. However, the extent to which the phenotypic effects of common and rare variants involve shared molecular mediators remains poorly understood. The question is essential to the basic and translational goals of the science of genomics, with critical basic-science, methodological, and clinical consequences. Leveraging the latest release of whole-exome sequencing (WES, for rare variants) and genome-wide association study (GWAS, for common variants) data from the UK Biobank, we developed a metric, the COmmon variant and RAre variant Convergence (CORAC) signature, to quantify the convergence for a broad range of complex traits. We characterized the relationship between CORAC and effective sample size across phenome-wide association studies. We found that the signature is positively correlated with effective sample size (Spearman ρ = 0.594, P < 2.2e - 16), indicating increased functional convergence of trait-associated genetic variation, across the allele frequency spectrum, with increased power. Sensitivity analyses, including accounting for heteroskedasticity and varying the number of detected association signals, further strengthened the validity of the finding. In addition, consistent with empirical data, extensive simulations showed that negative selection, in line with enhancing polygenicity, has a dampening effect on the convergence signature. Methodologically, leveraging the convergence leads to enhanced association analysis. The presented framework for the convergence signature has important implications for fine-mapping strategies and drug discovery efforts. In addition, our study provides a blueprint for the expectation from future large-scale whole-genome sequencing (WGS)/WES and sheds methodological light on post-GWAS studies.
Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors
Authors: Pere Llinàs-Arias, Miquel Ensenyat-Mendez, Sandra Íñiguez-Muñoz, Javier I. J. Orozco, Betsy Valdez, Matthew P. Salomon, Chikako Matsuba, Maria Solivellas-Pieras, Andrés F. Bedoya-López, Borja Sesé, Anja Mezger, Mattias Ormestad, Fernando Unzueta, Siri H. Strand, Alexander D. Boiko, E Shelley Hwang, Javier Cortés, Maggie L. DiNome, Manel Esteller, Mathieu Lupien, Diego M. Marzese
Journal: Molecular Cancer (2023)

Abstract Background Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process. Methods We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens. Results We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1.57 [1.06 − 2.33]; p = 0.023) and overall (HR = 2.65 [1.31 − 5.37], p = 0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0.77, p &lt; 0.01). Conclusion Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.
Chronic lymphocytic leukemia patient-derived xenografts recapitulate clonal evolution to Richter transformation
Authors: Heribert Playa-Albinyana, Fabian Arenas, Romina Royo, Ariadna Giró, Irene López-Oreja, Marta Aymerich, Mònica López-Guerra, Gerard Frigola, Sílvia Beà, Julio Delgado, Pablo M. Garcia-Roves, Elías Campo, Ferran Nadeu, Dolors Colomer
Journal: Leukemia (2023)

Abstract Chronic lymphocytic leukemia (CLL) is a B-cell neoplasm with a heterogeneous clinical behavior. In 5–10% of patients the disease transforms into a diffuse large-B cell lymphoma known as Richter transformation (RT), which is associated with dismal prognosis. Here, we aimed to establish patient-derived xenograft (PDX) models to study the molecular features and evolution of CLL and RT. We generated two PDXs by injecting CLL (PDX12) and RT (PDX19) cells into immunocompromised NSG mice. Both PDXs were morphologically and phenotypically similar to RT. Whole-genome sequencing analysis at different time points of the PDX evolution revealed a genomic landscape similar to RT tumors from both patients and uncovered an unprecedented RT subclonal heterogeneity and clonal evolution during PDX generation. In PDX12, the transformed cells expanded from a very small subclone already present at the CLL stage. Transcriptomic analysis of PDXs showed a high oxidative phosphorylation (OXPHOS) and low B-cell receptor (BCR) signaling similar to the RT in the patients. IACS-010759, an OXPHOS inhibitor, reduced proliferation, and circumvented resistance to venetoclax. In summary, we have generated new RT-PDX models, one of them from CLL cells that mimicked the evolution of CLL to RT uncovering intrinsic features of RT cells of therapeutical value.
SRSF2 mutation cooperates with ASXL1 truncated alteration to accelerate leukemogenesis
Authors: Pinpin Sui, Guo Ge, Shi Chen, Jiaojiao Bai, Ivan P. Rubalcava, Hui Yang, Ying Guo, Peng Zhang, Ying Li, Edward A. Medina, Mingjiang Xu, Omar Abdel-Wahab, Robert Bradley, Feng-Chun Yang
Journal: Leukemia (2023)
Sex-associated differences in frequencies and prognostic impact of recurrent genetic alterations in adult acute myeloid leukemia (Alliance, AMLCG)
Authors: Michael Ozga, Deedra Nicolet, Krzysztof Mrózek, Ayse S. Yilmaz, Jessica Kohlschmidt, Karilyn T. Larkin, James S. Blachly, Christopher C. Oakes, Jill Buss, Christopher J. Walker, Shelley Orwick, Vindi Jurinovic, Maja Rothenberg-Thurley, Annika Dufour, Stephanie Schneider, Maria Cristina Sauerland, Dennis Görlich, Utz Krug, Wolfgang E. Berdel, Bernhard J. Woermann, Wolfgang Hiddemann, Jan Braess, Marion Subklewe, Karsten Spiekermann, Andrew J. Carroll, William G. Blum, Bayard L. Powell, Jonathan E. Kolitz, Joseph O. Moore, Robert J. Mayer, Richard A. Larson, Geoffrey L. Uy, Wendy Stock, Klaus H. Metzeler, H. Leighton Grimes, John C. Byrd, Nathan Salomonis, Tobias Herold, Alice S. Mims, Ann-Kathrin Eisfeld
Journal: Leukemia (2023)

Abstract Clinical outcome of patients with acute myeloid leukemia (AML) is associated with demographic and genetic features. Although the associations of acquired genetic alterations with patients’ sex have been recently analyzed, their impact on outcome of female and male patients has not yet been comprehensively assessed. We performed mutational profiling, cytogenetic and outcome analyses in 1726 adults with AML (749 female and 977 male) treated on frontline Alliance for Clinical Trials in Oncology protocols. A validation cohort comprised 465 women and 489 men treated on frontline protocols of the German AML Cooperative Group. Compared with men, women more often had normal karyotype, FLT3 -ITD, DNMT3A , NPM1 and WT1 mutations and less often complex karyotype, ASXL1 , SRSF2 , U2AF1 , RUNX1 , or KIT mutations. More women were in the 2022 European LeukemiaNet intermediate-risk group and more men in adverse-risk group. We found sex differences in co-occurring mutation patterns and prognostic impact of select genetic alterations. The mutation-associated splicing events and gene-expression profiles also differed between sexes. In patients aged &lt;60 years, SF3B1 mutations were male-specific adverse outcome prognosticators. We conclude that sex differences in AML-associated genetic alterations and mutation-specific differential splicing events highlight the importance of patients’ sex in analyses of AML biology and prognostication.